Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
  • C07C29/09—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis
  • C07C29/095—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of esters of organic acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B57/00—Separation of optically-active compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C67/00—Preparation of carboxylic acid esters
  • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C67/00—Preparation of carboxylic acid esters
  • C07C67/48—Separation; Purification; Stabilisation; Use of additives
  • C07C67/60—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to chemical modification
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers

Definitions

• the present invention relates to a method for producing optically active fluorinated benzyl alcohol, which is an important intermediate of medicine.
• Non-Patent Document 1 A method for producing optically active fluorinated benzyl alcohol by optically resolving phthalic acid half ester of racemic fluorinated benzyl alcohol with optically active 1-phenylamine, and then hydrolyzing the ester group.
• Non-Patent Document 1 and Non-Patent Document 2 disclose the following method as a preparation method of “phthalic half ester of racemic fluorine-containing benzyl alcohol” which is a starting compound of the method. Yes.
• Non-Patent Document 1 a fluorine-containing benzaldehyde is reacted with an alkyl Grignard reagent to obtain a magnesium alkoxide of a racemic fluorine-containing benzyl alcohol, and then the magnesium alkoxide is converted to a racemic fluorine-containing vector.
• the racemic fluorine-containing benzyl alcohol is once isolated and purified, and then reacted with phthalic anhydride under basic conditions (the following scheme).
• Non-Patent Document 2 a method in which an aliphatic aldehyde is converted to magnesium alkoxide of a racemic fluorine-containing benzyl alcohol by reacting with a fluorine-containing ferroglycinal reagent and subsequently directly reacted with phthalic anhydride. Is adopted (the following scheme).
• Non-Patent Document 1 Journal of the American Chemical Society (USA), 1990, No. 112, No. 15, p. 5741-5747
• Non-Patent Document 2 Journal of the American Chemical Society (USA), 1985, No. 107, No. 15, p. 4513 -4519
• An object of the present invention is to provide an efficient optical resolution method for fluorine-containing benzyl alcohol which is an important pharmaceutical intermediate.
• the method of optical resolution of “racemic fluorine-containing benzyl alcohol phthalate phthalate” with optically active 1-phenylethylamine followed by hydrolysis of the ester group is optical regardless of the substitution position of the fluorine-containing substituent.
• it is important as a method with a wide substrate application range.
• Non-Patent Document 1 the preparation methods described in Non-Patent Document 1 and Non-Patent Document 2 say that the "phthalic half ester of racemic fluorine-containing benzyl alcohol" cannot be prepared easily and in good yield. There was a problem.
• the synthesis of “racemic fluorine-containing benzyl alcohol” and the synthesis of “phthalic acid half ester” are carried out separately, and the operation is very complicated due to the technical implementation. [Total yield based on 2-trifluoromethylbenzaldehyde was 61% (RMgX is CH MgBr)]
• Non-Patent Document 2 since the magnesium alkoxide generated in the reaction system is directly reacted with phthalic anhydride without isolating racemic fluorine-containing benzyl alcohol, the operation is remarkably simple. .
• “magnesium alkoxide of racemic fluorine-containing benzyl alcohol” derived from an aliphatic aldehyde and a fluorine-containing ferrigninal reagent does not show good reactivity with phthalic anhydride.
• Benzyl alcohol phthalic acid half ester was not obtained in good yield.
• the total yield based on [3-trifluoromethylphenol magnesium bromide (3-trifluoromethylphenol bromide) was 43%. (Aliphatic aldehyde is CH CHO)]
• the present inventors have converted fluorine-containing benzaldehyde to magnesium alkoxide of racemic fluorine-containing benzyl alcohol by reacting with alkyl Grignard reagent, and subsequently.
• the phthalic acid half ester of racemic fluorine-containing benzyl alcohol is very simple and good in yield (preferably 80% or more based on fluorine-containing benzaldehyde, It was further found that it can be prepared with a total yield of 90% or more.
• Non-Patent Document 2 The reason why the yield can be improved compared to Non-Patent Document 2 is that side reactions such as deprotonation of ⁇ -position protons and addition to carbonyl groups with magnesium alkoxide of the racemic fluorine-containing benzyl alcohol produced. It is thought that it is easy to wake up because “aliphatic aldehyde” should not be used. In Non-Patent Document 2, a substantial amount of racemic fluorine-containing benzyl alcohol is actually recovered (total yield 28%), and the reactivity to phthalic anhydride is drastically reduced through the side reaction. It is considered a thing.
• the present inventors further optically resolve the obtained half ester with optically active 1-phenylamine, and then hydrolyze the ester group, thereby obtaining the target optically active fluorine-containing ben It was also found that zircanol can be produced optically and chemically with extremely high purity (the following scheme).
• the present invention provides the formula [1] [Wherein, m represents the number of substituents on the fluorine atom, takes an integer selected from 0, 1, 2, 3, 4 or 5, n represents the number of substituents on the trifluoromethyl group, and 0, 1, 2 Or an integer selected from 3 and m and n cannot take 0 at the same time. The sum of m and n must be 5 or less.] Fluorine-containing benzaldehyde represented by the formula [2]
• R represents an alkyl group having 1 to 6 carbon atoms
• X represents a halogen atom selected from chlorine, bromine and iodine powers
• * represents an optically active substance, which may be a method for producing an optically active fluorinated benzyl alcohol (second method).
• a phthalic acid half ester of racemic fluorine-containing benzyl alcohol represented by [wherein the wavy line is the same as above] is obtained, and the half ester is optically resolved with optically active 1-phenylethylamine, and then By hydrolyzing the ester group, the formula [14] [Chemical 18]
• the present invention is characterized by a method for preparing a phthalic acid half ester of a racemic fluorine-containing benzyl alcohol.
• the half ester is easily obtained from fluorine-containing benzaldehyde at 80% or more (more preferably 90%). % Or more).
• optically active fluorinated benzyl alcohol can be produced efficiently.
• step I the step of reacting the fluorine-containing benzaldehyde represented by the formula [1] with the alkyl Grignard reagent represented by the formula [2] (step I) will be described.
• the fluorine atom or trifluoromethyl group of the fluorine-containing benzaldehyde represented by the formula [1] can take any substitution position, specifically, 2-fluorobenzaldehyde, 3 Fluorobenzaldehyde, 4 Fluorobenzaldehyde, 2, 4-Difluorobenzaldehyde, 2, 6 Difluorobenzaldehyde, 3, 5 Difluorobenzal Dehydr, 3, 4, 5 Trifluorobenzaldehyde, 2, 3, 4, 5, 6 Pentafluorobenzaldehyde, 2 Trifluoromethylbenzaldehyde, 3 Trifluoromethylbenzaldehyde, 4 Trifluoromethylbenzaldehyde, 3,5-bis (trifluoromethyl) benzaldehyde, 2 fluoro-3 trifluoromethylbenzaldehyde, 2 fluoro4 trifluoromethylbenzaldehyde, 2 fluoro-5 trifluoromethylbenzaldehy
• the optically active fluorinated benzyl alcohol represented by the formula [5], which is a subject of the present invention, can also be synthesized by asymmetric reduction of the corresponding fluorinated phenol alkyl ketone.
• the ketone is significantly more expensive than the fluorine-containing benzaldehyde that is the raw material substrate of the present invention, and the reaction between the aldehyde and the alkyl Grignard reagent represented by the formula [2] is a reduced product (ArCHOMgX (Ar is not contained).
• fluorine-containing benzaldehyde satisfying such requirements include those having a fluorine-containing substituent at the ortho position. Therefore, among the above specific examples, 2-fluorobenzaldehyde, 2,4-difluorobenzaldehyde, 2,6 difluorobenzaldehyde, 2, 3, 4, 5, 6 pentafluoro oral benzaldehyde, 2 Trifluoromethylbenzaldehyde, 2 fluoro-3 trifluoromethylbenzaldehyde, 2 fluoro-4 trifluoromethylbenzaldehyde, 2 fluoro-5 trifluoromethylbenzaldehyde, 2 fluoro-6 trifluoromethylbenzaldehyde, 3 fluoro-2 trif Fluoromethylbenzaldehyde, 3 fluoro 6-trifluoromethyl benzaldehyde and 4-fluoro 2 trifluoromethyl benzaldehyde are preferred, particularly 2-fluoro benzaldehyde, 2,4-di
• X of the alkyl Grignard reagent represented by the formula [2] is selected from chlorine, bromine and iodine.
• a racemic fluorinated benzyl alcohol alcohol alkoxide represented by the formula [3] and a phthalic anhydride derived from a fluorine-containing benzaldehyde represented by the formula [1] and an alkyl Grignard reagent It is particularly important to react well, and this reactivity is affected by the type of X. Accordingly, among the above halogen atoms, chlorine and bromine are preferred, and chlorine is more preferred because the magnesium alkoxide has higher nucleophilicity.
• alkyl Grignard reagent represented by the formula [2] a known method, for example, the 5th edition of the Japan Society for the Study of Experimental Chemistry, 18 Synthesis of Organic Compounds VI —Organic Synthesis Using Metals—p. 59—76 It can be prepared with reference to. Various constant-concentration ether solutions are commercially available, and it is easy to use them.
• the amount of the alkyl Grignard reagent represented by the formula [2] is not particularly limited, but is usually 0.7 mol or more with respect to 1 mol of the fluorine-containing benzaldehyde represented by the formula [1]. Is better, 0.8-1.2 monoreca is preferred, especially 0.9-1.1 monoreca! / ,. There is no particular problem even if the amount is less than 0.7 mol, but the fluorine-containing benzaldehyde remains unreacted, and the yield of the half-phthalate of racemic fluorine-containing benzyl alcohol represented by the formula [4] Shows a tendency to decrease. In addition, there is no particular problem with the use of 1.3 mol or more.
• the reaction solvent is not particularly limited, but is usually an ether solvent.
• ether solvent usually an ether solvent.
• jetyl ether, tetrahydrofuran, tert butyl methyl ether, di-pip pill ether, cyclopentyl methyl ether and 1,4 dioxane are particularly preferred.
• Jetyl ether, tetrahydrofuran, tert butyl methyl ether and di i Propyl ether is more preferred.
• These reaction solvents can be used alone or in combination.
• the amount of the reaction solvent used is not particularly limited, but it is usually sufficient to use 0.1 L (liter) or more per 1 mol of the fluorine-containing benzaldehyde represented by the formula [1]. 0.15 to 5 L is preferable, and 0.2 to 3 L is particularly preferable.
• a constant-concentration ether solution is used as the alkyl Grignard reagent represented by the formula [2]
• the reaction can be carried out using only the solvent contained in the ether solution without newly using a reaction solvent.
• the method for reacting the fluorine-containing benzaldehyde represented by the formula [1] with the alkyl Grignard reagent represented by the formula [2] is not particularly limited, but usually in an inert gas atmosphere, It is preferable to cool the ether solution of the alkyl Grignard reagent, gradually add fluorine-containing benzaldehyde (or a solution diluted with a reaction solvent) with stirring, and further carry out the reaction with stirring in a cooled state.
• the former method does not involve the by-product of the above reductant and the like, and the alkyl Grignard reagent is handled industrially safely. Is more preferable.
• the temperature condition is not particularly limited, but it is usually sufficient to be in the range of 100 to + 100 ° C. 80 to + 80 ° C is preferred. preferable.
• the reaction time is not particularly limited, but is usually within a range of 24 hours.
• the fluorine-containing benzaldehyde represented by the formula [1] and the alkyl grinder represented by the formula [2] When the fluorine-containing benzaldehyde remaining unreacted is traced by analytical means such as gas chromatography, liquid chromatography, or NMR, and the aldehyde almost disappears. U is the preferred end point,
• Step V the step of reacting the magnesium alkoxides of racemic fluorine-containing benzyl alcohol represented by the formula [3] with phthalic anhydride (Step V) will be described.
• the amount of phthalic anhydride used is not particularly limited, but it is usually sufficient to use 0.9 mol or more per 1 mol of the alkyl Grignard reagent represented by the formula [2]. 0.95 ⁇ : L 05 mol is preferred, and an equimolar amount is more preferred.
• reaction solvent is not particularly limited, but the above ether-based solvents are usually preferable.
• the amount of the reaction solvent used is not particularly limited, but usually the reaction solvent is not newly used and the reaction is completed after conversion to the magnesium alkoxide of racemic fluorine-containing benzyl alcohol represented by the formula [3]. It is preferable to carry out the reaction only with the solvent contained in the liquid.
• the method for reacting the magnesium alkoxide of the racemic fluorine-containing benzyl alcohol represented by the formula [3] with phthalic anhydride is not particularly limited, but usually the racemic fluorine-containing base is used in an inert gas atmosphere. It is preferable to cool the reaction-finished solution converted to magnesium alkoxide of benzyl alcohol, gradually add phthalic anhydride (or a solution diluted with a reaction solvent) with stirring, and further react at room temperature with stirring. .
• the method of adding the alkoxide to phthalic anhydride is not particularly problematic, but the former method is more preferable because it can employ an industrially simple one-pot reaction.
• the temperature condition there is no particular limitation on the temperature condition, but usually it should be performed in the range of 100 to + 100 ° C. 80 to + 80 ° C is preferred. preferable.
• the reaction time is not particularly limited, but is usually within a range of 24 hours.
• the post-treatment is not particularly limited, but usually an aqueous solution of a mineral acid (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, etc.) is added to the reaction completion solution, and an organic solvent (for example, toluene, methyl chloride) is added.
• a mineral acid for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, etc.
• an organic solvent for example, toluene, methyl chloride
• the desired phthalic acid half ester of racemic fluorine-containing benzyl alcohol represented by the formula [4] can be obtained by extraction with ethyl acetate or the like. Also if necessary And purified to high chemical purity by activated carbon treatment, recrystallization, distillation or column chromatography.
• Non-Patent Document 1 or Non-Patent Document 2. Therefore, the present invention is not limited to the following representative production methods.
• the phthalic acid half ester of racemic fluorine-containing benzyl alcohol represented by the formula [4] is brought into contact with the optically active 1-phenylethylamine to obtain the formula [15].
• m represents the number of substituents of the fluorine atom, takes an integer selected from 0, 1, 2, 3, 4 or 5; n represents the number of substituents of the trifluoromethyl group; Take an integer selected from 1, 2 or 3 and m and n cannot take 0 at the same time.
• the sum of m and n takes 5 or less.
• R represents an alkyl group having 1 to 6 carbon atoms.
• optically active fluorine-containing benzyl alcohol phthalate naphthoester represented by [where m, n, R and * are the same as above] is recovered (step III-C), and finally basic Under the condition, the ester group is hydrolyzed to produce an optically active fluorinated benzyl alcohol represented by the formula [5] (step m-D).
• Step III A will be described.
• the crystal precipitation solvent may contain the half-ester and the amine.
• the solution was dissolved by heating at a temperature near the boiling point of the solvent, and allowed to cool gradually while standing or stirring, and crystals were sufficiently precipitated in the range of 30 to + 30 ° C over 1 to 48 hours.
• a diastereomeric salt comprising optically active fluorinated benzyl alcohol phthalic acid half ester of formula [15] and optically active 1-phenylethylamine can be obtained.
• optical activity is obtained in the recovered organic layer obtained by extracting the phthalic acid half ester of racemic fluorine-containing benzyl alcohol represented by the formula [4] obtained by the post-treatment in Step II. More preferred is a method in which 1-phenylethylamine (or a solution diluted with a crystal precipitation solvent) is added to precipitate crystals.
• the filtrate contains an excessive amount of fluorine-containing benzyl alcohol phthalate having the opposite stereochemistry (or the half ester and diastereomeric salt having optically active 1-phenylethylamine power).
• the concentrated residue of the filtrate is subjected to the same operation as in Step ⁇ -C to obtain a half-phthalic ester of optically active fluorinated benzyl alcohol represented by the formula [16], which has the opposite stereochemistry. It can be recovered.
• R-form or S-form is appropriately used according to the target stereochemistry of the optically active fluorinated benzyl alcohol represented by the formula [5]. Use it properly.
• optical purity of 1-phenylethylamine should be 95% enantiomeric excess (ee) or higher, preferably 97% ee or higher, particularly 99% ee or higher. More preferred.
• the amount of optically active 1-phenylethylamine used should be 0.2 mol or more per 1 mol of phthalic acid half ester of racemic fluorine-containing benzyl alcohol represented by the formula [4]. 0.3-3 mol is preferred, and 0.4-1.5 mol is more preferred.
• crystal precipitation solvent examples include aliphatic hydrocarbons such as n-pentane, n-hexane, cyclohexane, and n-heptane, aromatic hydrocarbons such as benzene, toluene, ethylbenzene, xylene, and mesitylene.
• Halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane, etc., jetinoreethenole, tetrahydrofuran, tert-butinolemethinoreether, di-i-propyl ether, cyclopentylmethyl ether, 1, 4 Ethers such as dioxane, ketones such as acetone, methyl ethyl ketone and methyl i-butyl ketone, esters such as ethyl acetate and n- butyl acetate, -tolyls such as acetonitrile and propio-tolyl, methanol, ethanol, n Examples include alcohols such as --propanol, i-propanol, and n-butanol, and water.
• These crystal precipitation solvents can be used alone or in combination.
• the amount of the crystal precipitation solvent used is racemic fluorine-containing benzyl alcohol represented by the formula [4]. If 0.1 L or more is used per 1 mol of phthalic acid half ester, 0.2 to 10 L is preferable, and 0.3 to 7 L is more preferable.
• Step III B will be described.
• An optically active fluorine-containing benzyl alcohol phthalate half ester represented by the formula [15] and an optically active diastereomeric salt having a 1-phenylethylamine power can be recrystallized and purified by using a recrystallization solvent.
• the diastereomeric salt can be purified to a higher optical purity by sufficiently precipitating the crystals in the range of + 30 ° C. over 1 to 48 hours and filtering the precipitated crystals. By repeating this step, it can be further purified to high optical purity.
• the recrystallized mother liquor can also be recovered and reused according to a standard method.
• the crystal precipitation solvent of Step III-A can be used.
• the amount of the recrystallization solvent used is the same as the amount of the crystal precipitation solvent used in Step IV-A.
• Step III C will be described.
• An optically active fluorine-containing benzyl alcohol phthalate half ester represented by the formula [15] and a diastereomeric salt having an optically active 1-phenylethylamine force are brought into contact with a strong acid.
• the diastereomeric salt is added to and sufficiently shaken and extracted with an organic solvent, whereby the optically active fluorinated benzyl alcohol phthalic acid half ester represented by the formula [16] can be recovered.
• Examples of the inorganic acid include hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid and the like. Of these, hydrogen chloride and sulfuric acid are preferred, and especially hydrogen chloride hydrogen is more preferred.
• the amount of the inorganic acid used is 0 with respect to 1 mol of diastereomer monosalt composed of phthalic acid half ester of optically active fluorinated benzyl alcohol represented by formula [15] and optically active 1-phenylethylamine. It is better to use 7 mol or more. 0.8 to 7 mol is preferred. Especially 0.9 to 5 monoreca! / !.
• the concentration of the aqueous solution of the inorganic acid should be 0.3 normality (N) or more, preferably 0.4 to 7N, and more preferably 0.5 to 5N.
• organic solvent examples include toluene, methylene chloride, ethyl acetate and the like. Of these, toluene and ethyl acetate are preferred, and toluene is more preferred. These organic solvents can be used alone or in combination.
• the amount of the organic solvent used is 0 with respect to 1 mole of diastereomeric salt composed of phthalic acid half ester of optically active fluorinated benzyl alcohol represented by formula [15] and optically active 1-phenylethylamine. If 1L or more is used, 0.2-7L is preferable, and 0.3-5L is more preferable.
• the recovered organic layer obtained by extracting the optically active fluorinated benzyl alcohol phthalate and monoester of the formula [16] is washed with water, dried and concentrated as necessary. Although it is possible to isolate one fest, it is more preferable to add an aqueous solution of the inorganic base of Step IIID directly to the recovered organic layer to hydrolyze the ester group, from an industrial viewpoint.
• the optically active 1-phenylethylamine contained in the acidic aqueous layer can be recovered according to a conventional neutralization extraction and reused as the amine in Step III-A.
• Step III D will be described.
• the optically active fluorine-containing benzyl alcohol phthalate half ester represented by the formula [16] an isolated product or a recovered organic layer obtained by extraction as described above can be used.
• the reaction can also be carried out in a two-phase system.
• the reaction rate can be accelerated using a phase transfer catalyst such as a quaternary ammonium or phosphonium halide as necessary. You can also.
• suitable reaction conditions in this step good reactivity can be obtained without necessarily using the catalyst.
• Examples of the inorganic base include lithium carbonate, sodium carbonate, potassium carbonate, lithium hydroxide, water Acid sodium, potassium hydroxide and the like can be mentioned. Of these, lithium hydroxide, sodium hydroxide and potassium hydroxide are preferred, and sodium hydroxide and potassium hydroxide are more preferred.
• the amount of the inorganic base used may be 1.7 mol or more per 1 mol of the phthalic acid half ester of the optically active fluorine-containing benzyl alcohol represented by the formula [16] 1.8 ⁇ 15 Monoreka is preferred, especially 1.9 ⁇ 10 Monoreca is preferred!
• the concentration of the aqueous solution of the inorganic base is preferably 0.5N or more, preferably 0.7 to 15N, particularly 1 to: LON is more preferable.
• reaction solvent examples include aromatic hydrocarbons such as benzene, toluene, ethylbenzene, xylene, and mesitylene, halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane, jetyl ether, tetrahydrofuran, tert-butyl methyl ether, di-i-propyl ether, cyclopentyl methyl ether, 1, 4 Jiokisan like E one ether system, Asetonitoriru, propionate - a tolyl - tolyl based, methanol, ethanol, n-propanol, i-propanol, n- Examples include alcohols such as butanol and water.
• aromatic hydrocarbons such as benzene, toluene, ethylbenzene, xylene, and mesitylene
• halogenated hydrocarbons such as methylene chloride, chloroform,
• toluene, xylene, methylene chloride, tetrahydrofuran, and tert-butyl are particularly preferred, with toluene, xylene, mesitylene, methylene chloride, tetrahydrofuran, tert-butyl methyl ether, di-propyl ether, acetonitrile, methanol, ethanol and i-propanol being preferred. More preferred are methyl ether, acetonitrile, methanol and i-propanol.
• reaction solvents can be used alone or in combination.
• the reaction solvent may be used in an amount of 0.1 L or more with respect to 1 mol of the phthalic acid half ester of the optically active fluorine-containing benzyl alcohol represented by the formula [16].
• the temperature condition may be 30 to + 150 ° C, preferably 20 to + 125 ° C, more preferably -10 to + 100 ° C.
• the reaction time may be within a range of 24 hours.
• the optical activity represented by the formula [16] Optics that remain unreacted by analytical means such as gas chromatography, liquid chromatography, NMR, etc., depending on the combination of the phthalic acid half ester of fluorine-containing benzyl alcohol and the aqueous solution of the inorganic base and the reaction conditions. It is preferable to trace the phthalic acid half ester of the active fluorine-containing benzyl alcohol, and set the end point when the half ester has almost disappeared.
• the reaction end solution is directly separated or extracted by adding an organic solvent such as toluene, methylene chloride, and ethyl acetate or water to the reaction end solution as necessary.
• an organic solvent such as toluene, methylene chloride, and ethyl acetate or water
• the target optically active fluorinated benzyl alcohol represented by the formula [5] can be produced. If necessary, it can be purified to a high chemical purity and optical purity by treatment with activated carbon, recrystallization, distillation, column chromatography, or the like.
• (S) -1 mono (2 fluorophenyl) ethyl alcohol represented by the formula (1) was obtained.
• the alcohol was fractionally distilled (58 ° C., Z530 Pa) to obtain 63.5 g of a distilled and purified product of (S) -1 mono (2 fluorophenol) ethyl alcohol represented by the above formula.
• the optical purity of the purified product was measured by chiral gas chromatography to be 99.3% ee.
• the chemical purity of the purified product was 99.9% as measured by gas chromatography.
• (S) -l- (2 fluorophenyl) ethyl alcohol phthalic acid half ester was obtained.
• nitromethylbenzaldehyde 174.lg (2. trifluoromethylbenzaldehyde) was cooled under a nitrogen atmosphere while cooling 500mL (1.OOmol, 1.OOeq) of OM methylmagnesium chloride in tetrahydrofuran and controlling the internal temperature to 4-21 ° C. l. OOmol, 1. OOeq) was added, and the mixture was stirred for 15 minutes while cooling with ice water. The conversion rate of methyl candy was measured by gas chromatography and found to be 99.9% or more. Subsequently, 148.lg of phthalic anhydride (l.
• (S) -1-Fe-lethylamine diastereomeric salt has a total yield of 89.6. %Met.
• the 1 H-NMR and 19 F-NMR spectra of the obtained (S) -1 (2 trifluoromethylphenol) ethyl alcohol are shown below.

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